Variations in the temporal pattern of perforant pathway stimulation control the activity in the mesolimbic pathway

Signal processing in the hippocampal formation and resultant signal propagation to cortical and subcortical structures during high frequency stimulation (i.e. 100 Hz) of the perforant pathway was studied in medetomidine anesthetized rats by functional magnetic resonance imaging (fMRI) and electrophysiological recordings. The perforant pathway was stimulated with bursts of 20 pulses, one burst per second, or with continuously applied pulses. The stimulation duration was adjusted to 8 s (short) or 30 s (long). In general, extending the stimulation duration only caused a local spreading of the fMRI response, but no changes in the magnitude of the fMRI response. This was in agreement with the electrophysiological responses, which also remained unchanged. In contrast, increasing the number of pulses in one stimulus train (i.e. changing from burst to continuous stimulation), caused both spreading and an increase in local fMRI responses that were accompanied by an altered neuronal response pattern. Continuous stimulation also triggered additional fMRI responses in the septum, nucleus accumbens, anterior cingulate cortex/medial prefrontal cortex, and ventral tegmental area/substantia nigra. The appearance of fMRI responses outside the hippocampal formation required at least 3 consecutive stimulation trains, characterized by region specific hemodynamic response functions. Thus, once triggered, continuous stimulation caused a sequential appearance in fMRI responses starting in the hippocampal formation, followed by signal changes in the ventral tegmental area/substantia nigra and anterior cingulate cortex/medial prefrontal cortex and eventually in the nucleus accumbens. These results indicate that high frequency stimulation of the hippocampal formation can activate the mesolimbic pathway, provided that repetitive stimulations are applied.